Among HLA Class II antigens HLA-DR4 antigens have been extensively characterized because of their statistically significant, although not absolute, association with insulin dependent diabetes and rheumatoid arthritis. HLA-DR4 antigens indistinguishable with conventional antisera may be associated with structurally distinct HLA-DQw3 antigens, different HLA-D allospecificities and may display structural heterogeneity. Since the available information suggests that subtyping of HLA-DR4 antigens may improve the association with insulin dependent diabetes and with rheumatoid arthritis, this proposal aims at developing monoclonal antibodies which identify subtypes of HLA-DR4 and HLA-DQw3 antigens. Following an extensive characterization the anti HLA-DR4 and anti DQw3 antibodies will be used to develop double determinant immunoassays for HLA Class II typing and to develop antiidiotype antibodies. The latter in turn will be utilized to investigate the modulation of immune response to HLA Class II antigens and to quantitate antiidiotype antibodies in patients with diabetes mellitus and rheumatoid arthritis and in heart and renal transplant recipients. Lymphoid cells and sera will represent the antigen source. Available and newly developed hybridomas will represent the antibody sources. Immunochemical and cell mediated immunity tests will represent the assay systems. The results of these studies will contribute to the characterization of the clinical significance of HLA-DR4 and DQw3 heterogeneity and may suggest novel approaches to treat diseases with autoimmune pathogenesis.